Targeting PI3K-Akt-mTOR signalling in cancer
Hyo Song Kim, M.D., Ph.D.
Division of Medical Oncology Department of Internal Medicine
Yonsei Cancer Center
Overview of PI3K-Akt-mTOR pathway
Copyright by Rockland Immunochemicals
아담이 셋을 낳은 후
셋은 일백 오세에 에노스를 낳았고 에노스는 구십세에 게난을 낳았고 게난은 칠십세에 마할랄렐을 낳았고 마할랄렐은 육십 오세에 야렛을 낳았고 야렛은 일백 육십 이세에 에녹을 낳았고 에녹은 육십 오세에 므두셀라를 낳았고 므두셀라는 라멕을 낳았고
라멕은 일백 팔십 이세에 아들을 낳고 이름을 노아라 하여 가로되 여호와께서 땅을 저주하시므로 수고로이 일하는 우리를 이 아들이 안위하리라 하였더라 노아가 오백세 된 후에 셈과 함과 야벳 을 낳았더라
-창세기 5장 중에서-
Copyright by Rockland Immunochemicals
Overview of PI3K-Akt-mTOR pathway
PI3K-Akt-mTOR pathway
PI3K
PI3K: Phosphatidylinositol 3-kinase, mTOR: mammalian target of rapamycin
mTOR
J Clin Oncol 2010 Feb;28;6
Regulatory subunit
Catalytic subunit (gene)
p110α (PIK3CA) p110β (PIK3CB) p110γ (PIK3CG) p110δ (PIK3CD) PI3Kα
PI3Kβ PI3Kγ PI3Kδ
P85(PIK3R1)/54/
I
55II/III
(1) PI3K : structural classification of PI3K
Enzyme
Class
Fruman et al Nature Reviews 2014
(1) PI3K: input to PI3K signal
GPCR: G protein–coupled receptor
Targets and their roles
PI3K activation : genetic alterations
Rodon et al Nature reviews 2013
Clinical trials with PI3K inhibitors
www.nature.com/reviews/drugdisc
Pan-class I PI3K inhibitor
• Most cancer cells express multiple PI3K isoforms
• Concerns : “Blunt Tools”
– Doses to fully block all class might not be tolerated d/t toxicities – Common off-target effect
Pan-class I PI3K inhibitor: BKM120
• Phase I results
: Pan-PI3K inhibitor (α,β,γ, δ) with nano molar range (Novartis)
• Patients : 35 advanced solid tumors
• Toxicity
– DLT in 7/30 patients – Gr 4 hyperglycemia
– Gr 3 rash : maculopapular rash
– Gr 3 mood alteration (anxiety, euphoria, depression): reversible
Johanna et al J Clin Oncol 2011 DLT: dose-limiting toxicity, MTD: Maximum tolerated dose
Pan-class I PI3K inhibitor: BKM120
• Antitumor efficacy
– 1 Partial response : triple negative BC with KRAS mutation – 5/7 patients for ≥ 8 months with PI3K pathway dependence
Johanna et al J Clin Oncol 2011
PI3Kα-selective inhibitor
• PIK3CA PIK3CA PIK3CA PIK3CA gene gene gene gene
– Produce p110α catalytic subunit
– 2 hotspots of PIK3CA activating mutation
• H1047R (exon 20)
• E545K, E542K (exon 9)
Dam et al BMC cancer 2006
• Isoform selectivity
• For wild type : ERBB2, PIK3CA amplification, NRAS mutation
BYL719 shows robust efficacy in PIK3CA-mutant cancers
Fritsch et al Mol Cancer Ther 2014
PI3Kα-selective inhibitor: BYL719
Responder
• Phase I clinical trial with BYL719 (Jordi et al. AACR 2013) – Tumors with PIK3CA amplification or mutation (n=93) – DLT
• hyperglycemia and nausea – MTD : 400 mg3/day
– Antitumor efficacy
β-selectivity in PTEN deficiency
• PIK3CA depletion results in growth inhibition in PIK3CA mutation NOT PTEN deficient tumors
• PIK3CB inactivation inhibits
tumor growth in PTEN deficient tumor
Wee et al PNAS 2008
PIK3CA mutation (+) PTEN deficient
PTEN deficient
β inhibitors would be more effective in PTEN-deficient tumors
β-selective PI3K inhibitor
• Ongoing clinical trials
• Major inclusion criteria
– GSK2636771 : documented PTEN deficiency using IHC assay – AZD8186: PTEN-deficient tumor tissue for expansion cohort
Agent name Company Clinical trial phase
AZD8186 Astra-Zeneca 1
SAR260301 Sanofi 1
GSK2636771 GSK 1
β-selective PI3K inhibitor : GSK2636771
• Phase I trial (Arkenau et al 2014 ASCO) – 53 patients
– PTEN-negative by immunohistochemistry
– Endometrioid, CRPC, ovarian, NSCLC, GBM, TNBC Gastric, CRC, HNSCC, melanoma
• DLT : hypophosphatemia, hypocalcemia, elevated AST
• MTD : 400 mg, once-daily
CRC, colorectal cancer; CRPC, castrate-resistant prostate cancer; GBM, glioblastoma;
HNSCC, head and neck squamous-cell carcinoma; NSCLC, non-small-cell lung cancer; PD, pharmacodynamic;
PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; TNBC, triple-negative breast cancer
PI3Kδ inhibitor : Idelalisib
• Open label, phase 2 study, – 41 sites in U.S and Europe – 125 patients
• Patients and methods
– indolent non-Hodgkins’ lymphoma (NHL) – ≥ 2 prior systemic chemotherapies
– Refractory to rituximab/alkylating agents (less than PR or PD<6 months)
• Idelalisib
– Small molecule inhibitor of highly selective PI3Kδ – 150 mg twice daily
Gopal et al NEJM 2014
PI3Kδ inhibitor : Idelalisib
57% RR (71/125) 6% CR, 50% PR
Gopal et al NEJM 2014
Median PFS 11 months
Median Duration of Response 12.5 months
PI3Kδ inhibitor : Idelalisib
PI3K γ/δ inhibitor : IPI-145
• Phase I trial with hematologic malignancy (Julian et al 2014 AACR)
• Study scheme
PI3K γ/δ inhibitor : IPI-145
• Preliminary activity in indolent NHL – 73% Overall response rate
Julian et al 2014 AACR
PI3K γ/δ inhibitor : IPI-145
• Preliminary activity in Relapsed/refractory CLL
Julian et al 2014 AACR
Adverse Events : IPI-145
Julian et al 2014 AACR
Summary (1)
• The most effective therapeutic strategy is likely to depend on the particular mechanism of PI3K-Akt activation in cancer
• So far, preclinical and immature clinical data suggest PI3Kα-selective inhibitor may have efficacy for PIK3CA mutations
• Recent studies have suggested a prominent role for β-selective PI3K inhibitor in some PTEN-deficient cancers
• Phase II clinical trials of PI3Kδ inhibitor (idelalisib) showed dramatic response in patients with previously treated indolent non-hodgkin’s lymphoma
mTOR inhibitor
1965 Collection of rapamycin-producing soil bacterium on Rapa Nui
이스터섬, Rapa Nui
Rapamycin
mTOR inhibitor
• Rapamycin
– 1965 Collection of rapamycin-producing soil bacterium on Rapa Nui
– 1999 Approved for graft rejection due to IL-2 suppression – 2002 Anti-restenosis agent following coronary balloon
angioplasty
• Semi-synthetic rapamycin-analogue
– Temsirolimus (IV, Torisel; Pfizer) : MCL, RCC
– Everolimus (Oral, Afinitor; Novartis) : RCC, PNET
MCL: mantle cell lymphoma, RCC: renal cell carcinoma, PNET: pancreatic neuroendocrine tumor (PNET)
(1) Temsirolimus for MCL
• Open –label, phase III, multicenter trial
• 162 refractory mantle cell lymphoma (MCL)
Tem75 Tem25 Invest P value
PFS (months) 4.8 3.4 1.9 0.0009
OS (months) 11.1 8.8 9.5 0.3053
ORR 22% 6% 2% 0.0019
Hess et al JCO 2009
Temsirolimus is effective for refractory MCL
(2) Temsirolimus for RCC
• Phase III, randomized trial
• Patients
– Untreated
– poor-risk metastatic RCC
Temsirolimus is recommended for 1st line poor-risk RCC
Hudes et al NEJM 2007
Poor risk: at least 3 of 6 (L D H ≥1.5, Hb<WNL, corrected Ca>10, Time from Dx >1 year, Karnofsky 60-70, multiple metastasis)
P=0.008
P<0.001
P<0.001
(3) Everolimus for RCC
• Phase III, randomized, double-blind trial
• Patients : metastatic RCC progressed on tyrosine kinase inhibitor (TKI, sunitinib and/or sorafenib)
Motzer et al Lancet 2008
Everolimus is recommended after TKI in clear cell RCC
Everolimus Placebo P
Median PFS (months)
4.0 1.9 <0.001
Median OS
(months) Not reached 8.8 0.23
(4) Everolimus for pancreatic NET
• Phase 3, place-controlled, randomized trial
• Patients
– Advanced, low-grade or intermediate grade pancreatic NET – Prior antineoplastic treatment was permitted
Yao et al NEJM 2011
Everolimus is recommended for progressive, advanced PNET
(5) Everolimus combination
• Randomized, phase 3 trial
• HR+ breast cancer progressed with non-steroidal aromatase inhibitor
Baselga et al NEJM 2012
Addition of everolimus to endocrine therapy showed improved PFS
Addition of everolimus to endocrine therapy showed improved PFS
Summary
• The most effective therapeutic strategy is likely to depend on the particular mechanism of PI3K-Akt-mTOR activation in cancer
• PTEN terminates PI3K signaling by dephosphorylation and mTORC1 negatively feeds back to diminish PI3K activation
• PI3Kα-selective inhibitor may have efficacy for PIK3CA mutations, and PTEN-deficient cancers may be candidates for β-selective PI3K
inhibitor
• PI3Kδ inhibitor (idelalisib) showed dramatic response in patients with previously treated indolent NHL
• Rapalogues are useful in some advanced cancers and as adjuvant to hormone therapy
Thank you
• Structural clssification
Isoforms Coding genes Fx
I Ia : catalytic subunit (p110α,β,δ) + regulatory subunite (p85, p65, p55)
Ib: p110γ+p101
PIK3CA(p110α) PIK3CB(p110β) PIK3CD(p110δ)
PIK3R1 (p85) PIK3R2 (p54)
PIK3R3 (p55) Lipid
phosphorylation II
III
IV Protein (mTOR, ATM,
ATR, DNA-PK) phosphorylation
Regulatory subtunit Catalytic subunit
Genetic alterations of PI3K signaling
PTEN
PTEN-deficient tumors
• PTEN is a tumor suppressor that negatively regulates Akt signaling.
• PTEN-deficient tumors are known to susceptible to PI3Kβ inhibition (c.f. PTEN-WT susceptible to PI3Kα-i).
• GSK2636771 is a selective and potent inhibitor of PI3Kβ.
Enzyme IC50 (nM)
PI3Kβ 5.2 ± 2.9 PI3Kα >5,800*
PI3Kδ 58 ± 32
PI3Kγ >12,600*
PIK3C2B >20,000*
VPS34 6,310
DNA-PK >50,000 mTOR >50,000
Wee et al. PNAS 2008. Dbouk et al. PNAS 2010.
Dienstmann et al. Mol Cancer Ther 2014.
PTEN-null tumor
PIK3CB shRNA
GSK2636771
Patient selection: GSK2636771 in PTEN-deleted gastric cancer
Results
Gopal et al NEJM 2014
Gopal et al NEJM 2014
Figure 1 Domain structure of class IA and class IB PI3K isoforms
Biochemical Journal 2012 442, 465 Biochemical Journal 2012 442, 465 Biochemical Journal 2012 442, 465
Biochemical Journal 2012 442, 465----481 481 481 481 ---- Lomon So and DavidLomon So and DavidLomon So and David A. FrumanLomon So and DavidA. FrumanA. FrumanA. Fruman www.biochemj.org
Relevant drugs for PI3K/Akt/mTOR
Rodon et al Nat Rev Clin Oncol 2013
GSK2636771 : PI3K (p110β)
Overview of PI3K-Akt-mTOR pathway
Rapamycin
54
Methods
Study Design
• P3B115717 (NCT01458067) study design is detailed in Figure 2
CRC, colorectal cancer; CRPC, castrate-resistant prostate cancer; GBM, glioblastoma;
HNSCC, head and neck squamous-cell carcinoma; NSCLC, non-small-cell lung cancer; PD, pharmacodynamic;
PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; TNBC, triple-negative breast cancer
Figure 2. P3B115717: FTIH Study Design
• Single oral dose to test preclinical PK assumptions
• Continuous daily dosing
• 3+3 dose escalation with PD evaluation
• Mandatory biopsies for PD cohorts
• RECIST measurement
• Expansion cohorts with PD evaluation
• RECIST measurement
CRPC
CRC
Signal finding
(Endometrioid, Gastric, GBM, HNSCC, Melanoma,
NSCLC, Ovarian, TNBC)
Single dose 25 mg
Part 1 Part 2:
Dose Escalation
Part 3:
Expansion Cohorts
PD cohorts Dose
escalation safety cohorts
25 mg
500 mg
50 mg
100 mg
200 mg
350 mg
350 mg 200 mg
100 mg 50 mg
400 mg
• Preliminary efficacy – 1 PR, 16 SD
– 8 more than 6 months Tx
Arkenau et al Proc ASCO 2015 PR: partial response, SD: dose-limiting toxicity
PTEN deficiency ?
Pan-PI3K inhibitors
BKM120 Phase I, II Novartis GSK615 /
GSK1059615
Phase I GlaxoSmithKline
BAY 80-6946 Phase I Bayer Isoform-specific PI3K inhibitors
GSK2636771 PI3K (p110β) GlaxoSmithKline
BYL719 Phase I Novartis
PI3K–mTOR inhibitors
BEZ235 Novartis Phase I, II GSK1059615 GlaxoSmithKline Phase I
PKI-587/ PF-
05212384 PI3K, mTOR Pfizer
β-selective PI3K inhibitor in PTEN- deficient tumors
• PTEN is a tumor suppressor that negatively regulates Akt signaling.
• PTEN-deficient tumors are known to susceptible to PI3Kβ inhibition (c.f. PTEN-WT susceptible to PI3Kα-i).
• GSK2636771 is a selective and potent inhibitor of PI3Kβ.
Wee et al. PNAS 2008. Dbouk et al. PNAS 2010.
Dienstmann et al. Mol Cancer Ther 2014.
PTEN-null tumor
PIK3CB shRNA
Patient selection: GSK2636771 in PTEN-deleted cancer
